Tryptophan (Trp) is an essential amino acid required for the biosynthesis of proteins, nicotinic acid and neurotransmitter 5-hydroxytryptamine. Indoleamine 2,3-dioxygenase (also known as INDO or IDO) catalyzes the first and rate limiting step in the degradation of L-tryptophan to N-formylkynurenine. In human cells, IFN-γ stimulation induces activation of IDO, which leads to a depletion of tryptophan, thereby arresting the growth of tryptophan-dependent intracellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis. IDO activity also has an antiproliferative effect on many tumor cells, and IDO induction has been observed in vivo during rejection of aliogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process.
Small molecule inhibitors of IDO can be developed to treat or prevent IDO-related diseases. For example, PCT Publication WO 99/29310 reports methods of altering T cell-mediated immunity comprising altering local extracellular concentrations of tryptophan and tryptophan metabolites, using an inhibitors of IDO such as 1-methyl-DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benzo(b)thienyl]-DL-alanine, and 6-nitro-L-tryptophan) (Munn, 1999). Reported in WO 03/087347, are methods of making antigen-presenting cells for enhancing or reducing T cell tolerance (Munn, 2003). Compounds having indoleamine-2,3-dioxygenase (IDO) inhibitory activity are further reported in WO 2004/094409, WO 2009/073620, WO 2009/132238, WO 2011/056652 and WO 2012/142237. In particular, compounds in WO 2012/142237 comprise a series of tricyclic imidazoisoindoles with potent IDO inhibitory activity, including NLG-919 having the following formula:
